Fungitoxicity of Compounds Containing a Trichloromethylthio-Group

Carcinogenic mode of action of folpet in mice and evaluation of its relevance to humans

“…For the duodenal tumors induced in mice by folpet, the mode of action involves irritation-related cytotoxicity with consequent cellular regeneration ultimately leading to the development of tumors� The critical key event involves consumption of sufficiently high levels of folpet that yield a cytotoxic concentration of folpet and its degradation product, thiophosgene� Combined, these chemicals can cause cytotoxicity in the duodenum (Table 6)� In the stomach and duodenum there is cytotoxicity from the direct reaction of folpet with cellular components containing thiol groups as well as from the highly reactive thiophosgene, a hydrolysis product of folpet, which reacts with thiols as well as other cellular constituents (see Figures 1 and 2)� Folpet itself, like captan (Wilkinson et al�, 2004), is reactive with thiol groups, which generates thiophosgene (Figure 1)� However, thiophosgene is also reactive with thiol groups (Figure 2), with a half-life of less than 1 s (0�6 s in human blood)� Thiophosgene, thus, is generated either by the reaction of folpet with thiol groups or following hydrolysis of folpet� Direct interaction of folpet with thiol groups is the primary source of the thiophosgene� The hydrolysis of folpet to thiophosgene is highly pH dependent� The reaction occurs readily at neutral to alkaline pH but significantly less at low pH� Because of their marked reactivity, folpet and thiophosgene will react rapidly with thiol groups and not reach DNA or DNA-related targets (e�g�, histones) Liu and Fishbein, 1967;Lukens, 1966;Lukens et al�, 1965;Siegel, 1971aSiegel, , 1971bBernard and Gordon, 2000)� This is highlighted by a pair of key in vivo studies that show folpet and captan do not induce genotoxicity, as evidenced by the lack of increased nuclear aberrations in the tumor target site, the duodenum (Chidiac and Goldberg, 1987;Gudi and Krsmanovic, 2001)� Thus, DNA damage is highly unlikely and not detected in studies designed to assess this effect at the target tissue in vivo (Arce et al�, 2010)�…”

“…The reaction of folpet and thiophosgene with thiol groups in glutathione and proteins Siegel, 1972, 1977;Jernstrom et al, 1993;Liu and Fishbein, 1967;Lukens, 1966;Lukens et al�, 1965;Moriya et al�, 1978;Siegel, 1971aSiegel, , 1971b leads to cytotoxicity and an inflammatory reaction, with a consequent regenerative increase in cell proliferation and ultimately the development of tumors (Figure 7)� The sequence of events involving cytotoxicity and regenerative proliferation is a common mode of action for tumorigenesis by non-DNA-reactive chemicals (Meek et al�, 2003)� Cytotoxicity and regeneration is the same mode of action that has been demonstrated for the duodenal tumors induced in mice by captan (Bernard and Gordon, 2000;Gordon, 2007;2010;US EPA, 2004a)� The mode of action for folpet, including generation of thiophosgene, is similar to that seen with chloroform� Chloroform is metabolically activated to phosgene, which leads to liver and kidney cytotoxicity, regeneration, and ultimately tumors� Like folpet, this is a threshold phenomenon (Andersen et al�, 2000;Meek et al�, 2003)� Thiophosgene is not available systemically based on the chemical reactivity of folpet in the gastrointestinal tract and thiophosgene's rapid degradation in blood, in contrast to the systemic distribution of chloroform and the enzymatic generation of phosgene� In contrast to chloroform, folpet is considerably less toxic, probably related to the rapid extracellular hydrolysis leading to thiophosgene, which must then react with cells, compared to the intracellular generation of phosgene by metabolism of chloroform� Exogenous exposure to phosgene by inhalation, a highly toxic event, is unrelated to the process of the intracellular generation of phosgene from chloroform�…”

Captan: Transition from ‘B2’ to ‘not likely’. How pesticide registrants affected the EPA Cancer Classification Update

“…With sufficient thiols, the mutagenicity was reduced to background levels (Moriya et al, 1978). The basis of this reduction is the rapid stoichiometric reaction of captan with thiols with the resultant degradation of the parent compound (Liu and Fishbein, 1967;Lukens, 1966).…”

Photodegradation of etridiazole by UV radiation during drinking water treatment

“…Compound 2 was found to be highly toxic on an acute basis (US EPA, 2000). The toxicity of compounds 5 and 6 was unknown, but their fungitoxicity can be expected to be lower due to the lack of trichloromethyl moiety which leads to the fungitoxicity of captan (Lukens, 1966). From safe-guarding the drinking water quality point of view, additional research about the chronic dietary risk of ETZ degradation byproducts to human health should be addressed in the future.…”